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Journal articles on the topic 'Pharmacological chaperones'

Author: Grafiati

Published: 4 June 2021

Last updated: 10 March 2023

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1

Tran, My Lan, Yves Génisson, Stéphanie Ballereau, and Cécile Dehoux. "Second-Generation Pharmacological Chaperones: Beyond Inhibitors." Molecules 25, no. 14 (July 9, 2020): 3145. http://dx.doi.org/10.3390/molecules25143145.

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Protein misfolding induced by missense mutations is the source of hundreds of conformational diseases. The cell quality control may eliminate nascent misfolded proteins, such as enzymes, and a pathological loss-of-function may result from their early degradation. Since the proof of concept in the 2000s, the bioinspired pharmacological chaperone therapy became a relevant low-molecular-weight compound strategy against conformational diseases. The first-generation pharmacological chaperones were competitive inhibitors of mutant enzymes. Counterintuitively, in binding to the active site, these inhibitors stabilize the proper folding of the mutated protein and partially rescue its cellular function. The main limitation of the first-generation pharmacological chaperones lies in the balance between enzyme activity enhancement and inhibition. Recent research efforts were directed towards the development of promising second-generation pharmacological chaperones. These non-inhibitory ligands, targeting previously unknown binding pockets, limit the risk of adverse enzymatic inhibition. Their pharmacophore identification is however challenging and likely requires a massive screening-based approach. This review focuses on second-generation chaperones designed to restore the cellular activity of misfolded enzymes. It intends to highlight, for a selected set of rare inherited metabolic disorders, the strategies implemented to identify and develop these pharmacologically relevant small organic molecules as potential drug candidates.

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2

Wright, Gareth S. A. "Molecular and pharmacological chaperones for SOD1." Biochemical Society Transactions 48, no. 4 (August 14, 2020): 1795–806. http://dx.doi.org/10.1042/bst20200318.

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The efficacy of superoxide dismutase-1 (SOD1) folding impacts neuronal loss in motor system neurodegenerative diseases. Mutations can prevent SOD1 post-translational processing leading to misfolding and cytoplasmic aggregation in familial amyotrophic lateral sclerosis (ALS). Evidence of immature, wild-type SOD1 misfolding has also been observed in sporadic ALS, non-SOD1 familial ALS and Parkinson's disease. The copper chaperone for SOD1 (hCCS) is a dedicated and specific chaperone that assists SOD1 folding and maturation to produce the active enzyme. Misfolded or misfolding prone SOD1 also interacts with heat shock proteins and macrophage migration inhibitory factor to aid folding, refolding or degradation. Recognition of specific SOD1 structures by the molecular chaperone network and timely dissociation of SOD1-chaperone complexes are, therefore, important steps in SOD1 processing. Harnessing these interactions for therapeutic benefit is actively pursued as is the modulation of SOD1 behaviour with pharmacological and peptide chaperones. This review highlights the structural and mechanistic aspects of a selection of SOD1-chaperone interactions together with their impact on disease models.

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3

Borie-Guichot, Marc, My Lan Tran, Yves Génisson, Stéphanie Ballereau, and Cécile Dehoux. "Pharmacological Chaperone Therapy for Pompe Disease." Molecules 26, no. 23 (November 29, 2021): 7223. http://dx.doi.org/10.3390/molecules26237223.

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Pompe disease (PD), a lysosomal storage disease, is caused by mutations of the GAA gene, inducing deficiency in the acid alpha-glucosidase (GAA). This enzymatic impairment causes glycogen burden in lysosomes and triggers cell malfunctions, especially in cardiac, smooth and skeletal muscle cells and motor neurons. To date, the only approved treatment available for PD is enzyme replacement therapy (ERT) consisting of intravenous administration of rhGAA. The limitations of ERT have motivated the investigation of new therapies. Pharmacological chaperone (PC) therapy aims at restoring enzymatic activity through protein stabilization by ligand binding. PCs are divided into two classes: active site-specific chaperones (ASSCs) and the non-inhibitory PCs. In this review, we summarize the different pharmacological chaperones reported against PD by specifying their PC class and activity. An emphasis is placed on the recent use of these chaperones in combination with ERT.

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4

Banford, Samantha, Thomas J. McCorvie, Angel L. Pey, and David J. Timson. "Galactosemia: Towards Pharmacological Chaperones." Journal of Personalized Medicine 11, no. 2 (February 7, 2021): 106. http://dx.doi.org/10.3390/jpm11020106.

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Galactosemia is a rare inherited metabolic disease resulting from mutations in the four genes which encode enzymes involved in the metabolism of galactose. The current therapy, the removal of galactose from the diet, is inadequate. Consequently, many patients suffer lifelong physical and cognitive disability. The phenotype varies from almost asymptomatic to life-threatening disability. The fundamental biochemical cause of the disease is a decrease in enzymatic activity due to failure of the affected protein to fold and/or function correctly. Many novel therapies have been proposed for the treatment of galactosemia. Often, these are designed to treat the symptoms and not the fundamental cause. Pharmacological chaperones (PC) (small molecules which correct the folding of misfolded proteins) represent an exciting potential therapy for galactosemia. In theory, they would restore enzyme function, thus preventing downstream pathological consequences. In practice, no PCs have been identified for potential application in galactosemia. Here, we review the biochemical basis of the disease, identify opportunities for the application of PCs and describe how these might be discovered. We will conclude by considering some of the clinical issues which will affect the future use of PCs in the treatment of galactosemia.

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5

Liguori, Ludovica, Maria Monticelli, Mariateresa Allocca, Bruno Hay Mele, Jan Lukas, Maria Vittoria Cubellis, and Giuseppina Andreotti. "Pharmacological Chaperones: A Therapeutic Approach for Diseases Caused by Destabilizing Missense Mutations." International Journal of Molecular Sciences 21, no. 2 (January 13, 2020): 489. http://dx.doi.org/10.3390/ijms21020489.

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The term “pharmacological chaperone” was introduced 20 years ago. Since then the approach with this type of drug has been proposed for several diseases, lysosomal storage disorders representing the most popular targets. The hallmark of a pharmacological chaperone is its ability to bind a protein specifically and stabilize it. This property can be beneficial for curing diseases that are associated with protein mutants that are intrinsically active but unstable. The total activity of the affected proteins in the cell is lower than normal because they are cleared by the quality control system. Although most pharmacological chaperones are reversible competitive inhibitors or antagonists of their target proteins, the inhibitory activity is neither required nor desirable. This issue is well documented by specific examples among which those concerning Fabry disease. Direct specific binding is not the only mechanism by which small molecules can rescue mutant proteins in the cell. These drugs and the properly defined pharmacological chaperones can work together with different and possibly synergistic modes of action to revert a disease phenotype caused by an unstable protein.

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6

Shioi, Ryuta, Fumika Karaki, Hiromasa Yoshioka, Tomomi Noguchi-Yachide, Minoru Ishikawa, Kosuke Dodo, Yuichi Hashimoto, Mikiko Sodeoka, and Kenji Ohgane. "Image-based screen capturing misfolding status of Niemann-Pick type C1 identifies potential candidates for chaperone drugs." PLOS ONE 15, no. 12 (December 14, 2020): e0243746. http://dx.doi.org/10.1371/journal.pone.0243746.

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Niemann-Pick disease type C is a rare, fatal neurodegenerative disorder characterized by massive intracellular accumulation of cholesterol. In most cases, loss-of-function mutations in the NPC1 gene that encodes lysosomal cholesterol transporter NPC1 are responsible for the disease, and more than half of the mutations are considered to interfere with the biogenesis or folding of the protein. We previously identified a series of oxysterol derivatives and phenanthridine-6-one derivatives as pharmacological chaperones, i.e., small molecules that can rescue folding-defective phenotypes of mutated NPC1, opening up an avenue to develop chaperone therapy for Niemann-Pick disease type C. Here, we present an improved image-based screen for NPC1 chaperones and we describe its application for drug-repurposing screening. We identified some azole antifungals, including itraconazole and posaconazole, and a kinase inhibitor, lapatinib, as probable pharmacological chaperones. A photo-crosslinking study confirmed direct binding of itraconazole to a representative folding-defective mutant protein, NPC1-I1061T. Competitive photo-crosslinking experiments suggested that oxysterol-based chaperones and itraconazole share the same or adjacent binding site(s), and the sensitivity of the crosslinking to P691S mutation in the sterol-sensing domain supports the hypothesis that their binding sites are located near this domain. Although the azoles were less effective in reducing cholesterol accumulation than the oxysterol-derived chaperones or an HDAC inhibitor, LBH-589, our findings should offer new starting points for medicinal chemistry efforts to develop better pharmacological chaperones for NPC1.

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7

Babizhayev, Mark A. "Designation of imidazole-containing dipeptides as pharmacological chaperones." Human & Experimental Toxicology 30, no. 7 (July 23, 2010): 736–61. http://dx.doi.org/10.1177/0960327110377526.

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We review the dichotomous regulatory roles of natural imidazole-containing peptidomimetics (N-acetylcarnosine [NAC], carcinine, non-hydrolized carnosine) in maintaining skin homeostasis that determines whether keratinocytes survive or undergo apoptosis in response to various insults and in the development of skin diseases. General strategies addressing common ground techniques to improve absorption of usually active chaperone proteins or their dipeptide inducer (usually poorly absorbed) compounds include encapsulation into hydrophobic carriers, combination with penetration enhancers, active electrical transport or chemical modification to increase hydrophobicity. A growing evidence is presented that demonstrates the ability of NAC (lubricant eye drops) or carcinine to act as pharmacological chaperones, or being synergistically coupled in patented formulations with another imidazole-containing peptidomimetic (such as, Leucyl-histidylhydrazide), to decrease oxidative stress and ameliorate oxidative and excessive glycation stress-related eye disease phenotypes, suggesting that the field of chaperone therapy might hold novel treatments for age-related cataracts, glaucoma, age-related macular degeneration (AMD), and ocular complications of diabetes (OCD). Current efforts are being directed towards exploring therapeutic approaches of pharmacological targeting and human drug delivery for chaperone molecules based on innovative patented strategies.

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8

Kettern, Nadja, Michael Dreiseidler, Riga Tawo, and Jörg Höhfeld. "Chaperone-assisted degradation: multiple paths to destruction." Biological Chemistry 391, no. 5 (May 1, 2010): 481–89. http://dx.doi.org/10.1515/bc.2010.058.

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Abstract Molecular chaperones are well known as facilitators of protein folding and assembly. However, in recent years multiple chaperone-assisted degradation pathways have also emerged, including CAP (chaperone-assisted proteasomal degradation), CASA (chaperone-assisted selective autophagy), and CMA (chaperone-mediated autophagy). Within these pathways chaperones facilitate the sorting of non-native proteins to the proteasome and the lysosomal compartment for disposal. Impairment of these pathways contributes to the development of cancer, myopathies, and neurodegenerative diseases. Chaperone-assisted degradation thus represents an essential aspect of cellular proteostasis, and its pharmacological modulation holds the promise to ameliorate some of the most devastating diseases of our time. Here, we discuss recent insights into molecular mechanisms underlying chaperone-assisted degradation in mammalian cells and highlight its biomedical relevance.

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9

Voronin, Mikhail V., Elena V. Abramova, Ekaterina R. Verbovaya, Yulia V. Vakhitova, and Sergei B. Seredenin. "Chaperone-Dependent Mechanisms as a Pharmacological Target for Neuroprotection." International Journal of Molecular Sciences 24, no. 1 (January 3, 2023): 823. http://dx.doi.org/10.3390/ijms24010823.

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Modern pharmacotherapy of neurodegenerative diseases is predominantly symptomatic and does not allow vicious circles causing disease development to break. Protein misfolding is considered the most important pathogenetic factor of neurodegenerative diseases. Physiological mechanisms related to the function of chaperones, which contribute to the restoration of native conformation of functionally important proteins, evolved evolutionarily. These mechanisms can be considered promising for pharmacological regulation. Therefore, the aim of this review was to analyze the mechanisms of endoplasmic reticulum stress (ER stress) and unfolded protein response (UPR) in the pathogenesis of neurodegenerative diseases. Data on BiP and Sigma1R chaperones in clinical and experimental studies of Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and Huntington’s disease are presented. The possibility of neuroprotective effect dependent on Sigma1R ligand activation in these diseases is also demonstrated. The interaction between Sigma1R and BiP-associated signaling in the neuroprotection is discussed. The performed analysis suggests the feasibility of pharmacological regulation of chaperone function, possibility of ligand activation of Sigma1R in order to achieve a neuroprotective effect, and the need for further studies of the conjugation of cellular mechanisms controlled by Sigma1R and BiP chaperones.

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10

Копытова, А. Э., М. А. Николаев, Д. А. Богданова, К. А. Сенкевич, Г. В. Байдакова, О. И. Большакова, С. В. Саранцева, et al. "Pharmacological chaperones glucocerebrosidase as treatment of Gaucher disease." Nauchno-prakticheskii zhurnal «Medicinskaia genetika», no. 7(216) (July 30, 2020): 83–84. http://dx.doi.org/10.25557/2073-7998.2020.07.83-84.

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Мутации в гене лизосомного фермента глюкоцереброзидазы (GBA), приводящие к дисфункции фермента глюкоцереброзидазы (GCase), в гомозиготном состоянии вызывают болезнь Гоше (БГ), а в гетерозиготном состоянии повышают риск развития болезни Паркинсона (БП). Обсуждается использование фармакологических шаперонов (ФШ) GСase для терапии как БГ, так и GBA-ассоциированной БП (GBA-БП). Используя ФШ амброксол мы показали увеличение ферментативной активности GCase и снижение концентрации лизосфинголипидов HexSph в культуре первичных макрофагов пациентов с БГ и GBA-БП. Впервые проведена оценка эффективности новых химических соединений, модификаций ранее описанного аллостерического ФШ. Gaucher disease (GD), caused by GBA mutations, encodes lysosomal enzyme glucocerebrosidase (GCase). Pharmacological chaperones could potentially enhance GCase activity and treat GD and PD linked to mutations in the GBA gene (GBA-PD). Using ABX as pharmacological chaperone for macrophages derived from GD and GBA-PD patients we observed significantly enhanced GCase activity and decrease of HexSph concentration. For the first time was evaluated the effectiveness of chemical modifications of the previously described allosteric pharmacological chaperone.

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11

Nakagome, Izumi, Atsushi Kato, Noriyuki Yamaotsu, Tomoki Yoshida, Shin-ichiro Ozawa, Isao Adachi, and Shuichi Hirono. "Design of a New α-1-C-Alkyl-DAB Derivative Acting as a Pharmacological Chaperone for β-Glucocerebrosidase Using Ligand Docking and Molecular Dynamics Simulation." Molecules 23, no. 10 (October 18, 2018): 2683. http://dx.doi.org/10.3390/molecules23102683.

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Some point mutations in β-glucocerebrosidase cause either improper folding or instability of this protein, resulting in Gaucher disease. Pharmacological chaperones bind to the mutant enzyme and stabilize this enzyme; thus, pharmacological chaperone therapy was proposed as a potential treatment for Gaucher disease. The binding affinities of α-1-C-alkyl 1,4-dideoxy-1,4-imino-d-arabinitol (DAB) derivatives, which act as pharmacological chaperones for β-glucocerebrosidase, abruptly increased upon elongation of their alkyl chain. In this study, the primary causes of such an increase in binding affinity were analyzed using protein–ligand docking and molecular dynamics simulations. We found that the activity cliff between α-1-C-heptyl-DAB and α-1-C-octyl-DAB was due to the shape and size of the hydrophobic binding site accommodating the alkyl chains, and that the interaction with this hydrophobic site controlled the binding affinity of the ligands well. Furthermore, based on the aromatic/hydrophobic properties of the binding site, a 7-(tetralin-2-yl)-heptyl-DAB compound was designed and synthesized. This compound had significantly enhanced activity. The design strategy in consideration of aromatic interactions in the hydrophobic pocket was useful for generating effective pharmacological chaperones for the treatment of Gaucher disease.

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12

Fan, Jian-Qiang. "A counterintuitive approach to treat enzyme deficiencies: use of enzyme inhibitors for restoring mutant enzyme activity." Biological Chemistry 389, no. 1 (January 1, 2008): 1–11. http://dx.doi.org/10.1515/bc.2008.009.

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Abstract Pharmacological chaperone therapy is an emerging counterintuitive approach to treat protein deficiencies resulting from mutations causing misfolded protein conformations. Active-site-specific chaperones (ASSCs) are enzyme active-site directed small molecule pharmacological chaperones that act as a folding template to assist protein folding of mutant proteins in the endoplasmic reticulum (ER). As a result, excessive degradation of mutant proteins in the ER-associated degradation (ERAD) machinery can be prevented, thus restoring enzyme activity. Lysosomal storage disorders (LSDs) are suitable candidates for ASSC treatment, as the levels of enzyme activity needed to prevent substrate storage are relatively low. In addition, ASSCs are orally active small molecules and have potential to gain access to most cell types to treat neuronopathic LSDs. Competitive enzyme inhibitors are effective ASSCs when they are used at sub-inhibitory concentrations. This whole new paradigm provides excellent opportunity for identifying specific drugs to treat a broad range of inherited disorders. This review describes protein misfolding as a pathophysiological cause in LSDs and provides an overview of recent advances in the development of pharmacological chaperone therapy for the diseases. In addition, a generalized guidance for the design and screening of ASSCs is also presented.

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13

Robben, Joris H., and Peter M. T. Deen. "Pharmacological Chaperones in Nephrogenic Diabetes Insipidus." BioDrugs 21, no. 3 (2007): 157–66. http://dx.doi.org/10.2165/00063030-200721030-00003.

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14

Underhaug, Jarl, Oscar Aubi, and Aurora Martinez. "Phenylalanine Hydroxylase Misfolding and Pharmacological Chaperones." Current Topics in Medicinal Chemistry 12, no. 22 (March 1, 2013): 2534–45. http://dx.doi.org/10.2174/1568026611212220008.

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15

Underhaug, Jarl, Oscar Aubi, and Aurora Martinez. "Phenylalanine Hydroxylase Misfolding and Pharmacological Chaperones." Current Topics in Medicinal Chemistry 999, no. 999 (March 1, 2013): 36–42. http://dx.doi.org/10.2174/15680266112129990077.

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16

Shin, Min Hyeon, and Hyun-Suk Lim. "Screening methods for identifying pharmacological chaperones." Molecular BioSystems 13, no. 4 (2017): 638–47. http://dx.doi.org/10.1039/c6mb00866f.

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17

Petäjä-Repo, Ulla E., and Jarkko J. Lackman. "Targeting opioid receptors with pharmacological chaperones." Pharmacological Research 83 (May 2014): 52–62. http://dx.doi.org/10.1016/j.phrs.2013.12.001.

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18

Wang, Ya-Juan, Xiao-Jing Di, and Ting-Wei Mu. "Using pharmacological chaperones to restore proteostasis." Pharmacological Research 83 (May 2014): 3–9. http://dx.doi.org/10.1016/j.phrs.2014.04.002.

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19

Clark, N. E., M. C. Metcalf, D. Best, G. W. J. Fleet, and S. C. Garman. "Pharmacological chaperones for human -N-acetylgalactosaminidase." Proceedings of the National Academy of Sciences 109, no. 43 (October 8, 2012): 17400–17405. http://dx.doi.org/10.1073/pnas.1203924109.

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20

Okuyama, Youta, Hisayo Jin, Hiroshi Kokubun, and Tomohiko Aoe. "Pharmacological Chaperones Attenuate the Development of Opioid Tolerance." International Journal of Molecular Sciences 21, no. 20 (October 13, 2020): 7536. http://dx.doi.org/10.3390/ijms21207536.

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Opioids are potent analgesics widely used to control acute and chronic pain, but long-term use induces tolerance that reduces their effectiveness. Opioids such as morphine bind to mu opioid receptors (MORs), and several downstream signaling pathways are capable of inducing tolerance. We previously reported that signaling from the endoplasmic reticulum (ER) contributed to the development of morphine tolerance. Accumulation of misfolded proteins in the ER induced the unfolded protein response (UPR) that causes diverse pathological conditions. We examined the effects of pharmacological chaperones that alleviate ER stress on opioid tolerance development by assessing thermal nociception in mice. Pharmacological chaperones such as tauroursodeoxycholic acid and 4-phenylbutyrate suppressed the development of morphine tolerance and restored analgesia. Chaperones alone did not cause analgesia. Although morphine administration induced analgesia when glycogen synthase kinase 3β (GSK3β) was in an inactive state due to serine 9 phosphorylation, repeated morphine administration suppressed this phosphorylation event. Co-administration of chaperones maintained the inactive state of GSK3β. These results suggest that ER stress may facilitate morphine tolerance due to intracellular crosstalk between the UPR and MOR signaling. Pharmacological chaperones may be useful in the management of opioid misuse.

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21

Loo, Tip W., and David M. Clarke. "Chemical and pharmacological chaperones as new therapeutic agents." Expert Reviews in Molecular Medicine 9, no. 16 (June 2007): 1–18. http://dx.doi.org/10.1017/s1462399407000361.

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Proteins that are exported from the cell, or targeted to the cell surface or other organelles, are synthesised and assembled in the endoplasmic reticulum and then delivered to their destinations. Point mutations – the most common cause of human genetic diseases – can inhibit folding and assembly of the protein in the endoplasmic reticulum. The unstable or partially folded mutant protein does not undergo trafficking and is usually rapidly degraded. A potential therapy for protein misfolding is to correct defective protein folding and trafficking using pharmacological chaperones. Pharmacological chaperones are substrates or modulators that appear to function by directly binding to the partially folded biosynthetic intermediate to stabilise the protein and allow it to complete the folding process to yield a functional protein. Initial clinical studies with pharmacological chaperones have successfully reduced clinical symptoms of disease. Therefore, pharmacological chaperones show great promise as a new class of therapeutic agents that can be specifically tailored for a particular genetic disease.

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22

Shevtsov, Maxim, Gabriele Multhoff, Elena Mikhaylova, Atsushi Shibata, Irina Guzhova, and Boris Margulis. "Combination of Anti-Cancer Drugs with Molecular Chaperone Inhibitors." International Journal of Molecular Sciences 20, no. 21 (October 24, 2019): 5284. http://dx.doi.org/10.3390/ijms20215284.

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Most molecular chaperones belonging to heat shock protein (HSP) families are known to protect cancer cells from pathologic, environmental and pharmacological stress factors and thereby can hamper anti-cancer therapies. In this review, we present data on inhibitors of the heat shock response (particularly mediated by the chaperones HSP90, HSP70, and HSP27) either as a single treatment or in combination with currently available anti-cancer therapeutic approaches. An overview of the current literature reveals that the co-administration of chaperone inhibitors and targeting drugs results in proteotoxic stress and violates the tumor cell physiology. An optimal drug combination should simultaneously target cytoprotective mechanisms and trigger the imbalance of the tumor cell physiology.

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23

Narita, Aya, Katsumi Higaki, José Manuel Garcia Fernández, and Carmen Ortiz Mellet. "pH-responsive pharmacological chaperones for lysosomal disease." Molecular Genetics and Metabolism 117, no. 2 (February 2016): S85—S86. http://dx.doi.org/10.1016/j.ymgme.2015.12.376.

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24

Bernier, Virginie, Monique Lagacé, Daniel G. Bichet, and Michel Bouvier. "Pharmacological chaperones: potential treatment for conformational diseases." Trends in Endocrinology & Metabolism 15, no. 5 (July 2004): 222–28. http://dx.doi.org/10.1016/j.tem.2004.05.003.

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25

Garman, Scott, Nathaniel E. Clark, and Matthew C. Metcalf. "Pharmacological chaperones for human alpha-N-acetylgalactosaminidase." Molecular Genetics and Metabolism 108, no. 2 (February 2013): S41. http://dx.doi.org/10.1016/j.ymgme.2012.11.090.

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26

Shin, Sang-Hoon, Gary J. Murray, Stefanie Kluepfel-Stahl, Adele M. Cooney, Jane M. Quirk, Raphael Schiffmann, Roscoe O. Brady, and Christine R. Kaneski. "Screening for pharmacological chaperones in Fabry disease." Biochemical and Biophysical Research Communications 359, no. 1 (July 2007): 168–73. http://dx.doi.org/10.1016/j.bbrc.2007.05.082.

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Alfonso, Pilar, Javier Gervas, Vanesa Andreu, Joaquin Navascues, Francisca Sanchez-Jimenez, Miguel Pocovi, Carmen Ortiz-Mellet, Jose M. Garcia-Fernandez, and Pilar Giraldo. "New Derivatives of L-Idonojirimycin Working As Pharmacological Chaperones for the Treatment of Gaucher Disease." Blood 120, no. 21 (November 16, 2012): 3270. http://dx.doi.org/10.1182/blood.v120.21.3270.3270.

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Abstract Abstract 3270 Introduction: Many of the mutations of the lysosomal acid b-glucosidase (b-glucocerebrosidase) associated with Gaucher disease (GD) translate into enzymes that retain partial catalytic activity in vitro but exhibit impaired cellular trafficking as a consequence of aberrant folding. Current investigational therapeutic strategies for include the development of ligands of the enzyme capable of promoting those conformational changes that are required for efficient folding, restoring trafficking. Although somewhat counter intuitive, competitive inhibitors of this b-glucocerebrosidase, at subinhibitory concentrations, can increase steady-state lysosomal levels of active enzyme through this rescuing mechanism, acting as “pharmacological chaperones”. At the massive lysosomal substrate concentration, the inhibitor would be replaced from the active site of the enzyme and the metabolic activity recovered. However, most of the pharmacological chaperones under study are iminosugars that behave as broad spectrum inhibitors, inhibiting simultaneously several glucosidases, which represents a serious inconvenient for clinical applications. An additional problem is that iminosugars and their derivatives are not active as pharmacological chaperones for glucocerebrosidase mutations located outside the domain containing the active site and are associated with neurological involvement, as the L444P mutation. Aim: The aim of this work is to present molecules with a high binding specificity towards b-glucocerebrosidase, with a high ratio of chaperone versus inhibitor activity and capable of producing an increased in the levels of mutant enzymes associated with Gaucher disease, including mutations located outside the catalytic domain. Methods: Different bicyclic derivatives of L-idonojirimycin were designed and chemically synthesized from D-glucose after in silico structural analysis and identification of the most favorable molecular features to interact with the active site of glucocerebrosidase. The chaperone potential of these compounds was evaluated at different concentrations in vitro using a cell model of GDcarrying the more frequent mutations in Gaucher disease, namely N370S and L444P. (P201230804). Results: The obtained results showed an increase in b-glucocerebrosidase activity at various chaperone concentrations, ranging from 1.96 to 4.98 folds for the L444P mutant and from 2.01 to 3.06 folds for the N370S mutation. Comments: The bicyclic derivatives of L-idonojirimycin could be considered as a therapeutic alternative for GD, mainly in patients with mutations located outside the active site of the enzyme and associated with neurologic involvement. Disclosures: Giraldo: Actelion: Membership on an entity's Board of Directors or advisory committees; Genzyme: Research Funding; Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Boyd, Robert E., Gary Lee, Philip Rybczynski, Elfrida R. Benjamin, Richie Khanna, Brandon A. Wustman, and Kenneth J. Valenzano. "Pharmacological Chaperones as Therapeutics for Lysosomal Storage Diseases." Journal of Medicinal Chemistry 56, no. 7 (March 11, 2013): 2705–25. http://dx.doi.org/10.1021/jm301557k.

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29

Santos-Sierra, Sandra, Johannes Kirchmair, Anna M. Perna, Dunja Reiß, Kristina Kemter, Wulf Röschinger, Hartmut Glossmann, et al. "Novel pharmacological chaperones that correct phenylketonuria in mice." Human Molecular Genetics 21, no. 8 (January 13, 2012): 1877–87. http://dx.doi.org/10.1093/hmg/dds001.

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Small, S. A. "Pharmacological chaperones in the age of proteomic pathology." Proceedings of the National Academy of Sciences 111, no. 34 (August 13, 2014): 12274–75. http://dx.doi.org/10.1073/pnas.1413111111.

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31

Losada, Juan Camilo, Carlos J. Alméciga, and Janneth Gonzalez. "identification of pharmacological chaperones for mucopolysaccharidosis type IIIB." Molecular Genetics and Metabolism 129, no. 2 (February 2020): S101. http://dx.doi.org/10.1016/j.ymgme.2019.11.256.

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32

Hill, Chris H., Agnete H. Viuff, Samantha J. Spratley, Stéphane Salamone, Stig H. Christensen, Randy J. Read, Nigel W. Moriarty, Henrik H. Jensen, and Janet E. Deane. "Azasugar inhibitors as pharmacological chaperones for Krabbe disease." Chemical Science 6, no. 5 (2015): 3075–86. http://dx.doi.org/10.1039/c5sc00754b.

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33

Morello, Jean-Pierre, Michel Bouvier, Ulla E. Petäjä-Repo, and Daniel G. Bichet. "Pharmacological chaperones: a new twist on receptor folding." Trends in Pharmacological Sciences 21, no. 12 (December 2000): 466–69. http://dx.doi.org/10.1016/s0165-6147(00)01575-3.

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Mecozzi, Vincent J., Diego E. Berman, Sabrina Simoes, Chris Vetanovetz, Mehraj R. Awal, Vivek M. Patel, Remy T. Schneider, Gregory A. Petsko, Dagmar Ringe, and Scott A. Small. "Pharmacological chaperones stabilize retromer to limit APP processing." Nature Chemical Biology 10, no. 6 (April 20, 2014): 443–49. http://dx.doi.org/10.1038/nchembio.1508.

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35

Rísquez-Cuadro, Rocío, Reimi Matsumoto, Fernando Ortega-Caballero, Eiji Nanba, Katsumi Higaki, José Manuel García Fernández, and Carmen Ortiz Mellet. "Pharmacological Chaperones for the Treatment of α-Mannosidosis." Journal of Medicinal Chemistry 62, no. 12 (April 24, 2019): 5832–43. http://dx.doi.org/10.1021/acs.jmedchem.9b00153.

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Yilmazer, Buge, Z. Begum Yagci, Emre Bakar, Burcu Ozden, Kutlu Ulgen, and Elif Ozkirimli. "Investigation of novel pharmacological chaperones for Gaucher Disease." Journal of Molecular Graphics and Modelling 76 (September 2017): 364–78. http://dx.doi.org/10.1016/j.jmgm.2017.07.014.

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Mena-Barragán, Teresa, Aya Narita, Dino Matias, Gustavo Tiscornia, Eiji Nanba, Kousaku Ohno, Yoshiyuki Suzuki, Katsumi Higaki, José Manuel Garcia Fernández, and Carmen Ortiz Mellet. "pH-Responsive Pharmacological Chaperones for Rescuing Mutant Glycosidases." Angewandte Chemie 127, no. 40 (August 7, 2015): 11862–66. http://dx.doi.org/10.1002/ange.201505147.

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Mena-Barragán, Teresa, Aya Narita, Dino Matias, Gustavo Tiscornia, Eiji Nanba, Kousaku Ohno, Yoshiyuki Suzuki, Katsumi Higaki, José Manuel Garcia Fernández, and Carmen Ortiz Mellet. "pH-Responsive Pharmacological Chaperones for Rescuing Mutant Glycosidases." Angewandte Chemie International Edition 54, no. 40 (August 7, 2015): 11696–700. http://dx.doi.org/10.1002/anie.201505147.

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Campanella, Claudia, Andrea Pace, Celeste Caruso Bavisotto, Paola Marzullo, Antonella Marino Gammazza, Silvestre Buscemi, and Antonio Palumbo Piccionello. "Heat Shock Proteins in Alzheimer’s Disease: Role and Targeting." International Journal of Molecular Sciences 19, no. 9 (September 1, 2018): 2603. http://dx.doi.org/10.3390/ijms19092603.

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Among diseases whose cure is still far from being discovered, Alzheimer’s disease (AD) has been recognized as a crucial medical and social problem. A major issue in AD research is represented by the complexity of involved biochemical pathways, including the nature of protein misfolding, which results in the production of toxic species. Considering the involvement of (mis)folding processes in AD aetiology, targeting molecular chaperones represents a promising therapeutic perspective. This review analyses the connection between AD and molecular chaperones, with particular attention toward the most important heat shock proteins (HSPs) as representative components of the human chaperome: Hsp60, Hsp70 and Hsp90. The role of these proteins in AD is highlighted from a biological point of view. Pharmacological targeting of such HSPs with inhibitors or regulators is also discussed.

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Weber, Patrick, Martin Thonhofer, Summer Averill, Gideon J. Davies, Andres Gonzalez Santana, Philipp Müller, Seyed A. Nasseri, et al. "Mechanistic Insights into the Chaperoning of Human Lysosomal-Galactosidase Activity: Highly Functionalized Aminocyclopentanes and C-5a-Substituted Derivatives of 4-epi-Isofagomine." Molecules 25, no. 17 (September 3, 2020): 4025. http://dx.doi.org/10.3390/molecules25174025.

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Glycosidase inhibitors have shown great potential as pharmacological chaperones for lysosomal storage diseases. In light of this, a series of new cyclopentanoid β-galactosidase inhibitors were prepared and their inhibitory and pharmacological chaperoning activities determined and compared with those of lipophilic analogs of the potent β-d-galactosidase inhibitor 4-epi-isofagomine. Structure-activity relationships were investigated by X-ray crystallography as well as by alterations in the cyclopentane moiety such as deoxygenation and replacement by fluorine of a “strategic” hydroxyl group. New compounds have revealed highly promising activities with a range of β-galactosidase-compromised human cell lines and may serve as leads towards new pharmacological chaperones for GM1-gangliosidosis and Morquio B disease.

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Rodríguez-Lavado, Julio, Mario de la Mata, José L. Jiménez-Blanco, M. Isabel García-Moreno, Juan M. Benito, Antonio Díaz-Quintana, José A. Sánchez-Alcázar, et al. "Targeted delivery of pharmacological chaperones for Gaucher disease to macrophages by a mannosylated cyclodextrin carrier." Org. Biomol. Chem. 12, no. 14 (2014): 2289–301. http://dx.doi.org/10.1039/c3ob42530d.

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Stauffert, Fabien, Jenny Serra-Vinardell, Marta Gómez-Grau, Helen Michelakakis, Irene Mavridou, Daniel Grinberg, Lluïsa Vilageliu, et al. "Stereodivergent synthesis of right- and left-handed iminoxylitol heterodimers and monomers. Study of their impact on β-glucocerebrosidase activity." Organic & Biomolecular Chemistry 15, no. 17 (2017): 3681–705. http://dx.doi.org/10.1039/c7ob00443e.

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Skórzyńska-Dziduszko, Katarzyna, Żaneta Kimber-Trojnar, Jolanta Patro-Małysza, Agnieszka Stenzel-Bembenek, Jan Oleszczuk, and Bożena Leszczyńska-Gorzelak. "Heat Shock Proteins as a Potential Therapeutic Target in the Treatment of Gestational Diabetes Mellitus: What We Know so Far." International Journal of Molecular Sciences 19, no. 10 (October 17, 2018): 3205. http://dx.doi.org/10.3390/ijms19103205.

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Gestational diabetes mellitus (GDM) is a complex condition that involves a variety of pathological mechanisms, including pancreatic β-cell failure, insulin resistance, and inflammation. There is an increasing body of literature suggesting that these interrelated phenomena may arise from the common mechanism of endoplasmic reticulum (ER) stress. Both obesity-associated nutrient excess and hyperglycemia disturb ER function in protein folding and transport. This results in the accumulation of polypeptides in the ER lumen and impairs insulin secretion and signaling. Exercise elicits metabolic adaptive responses, which may help to restore normal chaperone expression in insulin-resistant tissues. Pharmacological induction of chaperones, mimicking the metabolic effect of exercise, is a promising therapeutic tool for preventing GDM by maintaining the body’s natural stress response. Metformin, a commonly used diabetes medication, has recently been identified as a modulator of ER-stress-associated inflammation. The results of recent studies suggest the potential use of chemical ER chaperones and antioxidant vitamins as therapeutic interventions that can prevent glucose-induced ER stress in GDM placentas. In this review, we discuss whether chaperones may significantly contribute to the pathogenesis of GDM, as well as whether they can be a potential therapeutic target in GDM treatment.

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Angenoorth, Thomas J. F., Julian Maier, Stevan Stankovic, Shreyas Bhat, Sonja Sucic, Michael Freissmuth, Harald H. Sitte, and Jae-Won Yang. "Rescue of Misfolded Organic Cation Transporter 3 Variants." Cells 12, no. 1 (December 22, 2022): 39. http://dx.doi.org/10.3390/cells12010039.

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Organic cation transporters (OCTs) are membrane proteins that take up monoamines, cationic drugs and xenobiotics. We previously reported novel missense mutations of organic cation transporter 3 (OCT3, SLC22A3), some with drastically impacted transport capabilities compared to wildtype. For some variants, this was due to ER retention and subsequent degradation of the misfolded transporter. For other transporter families, it was previously shown that treatment of misfolded variants with pharmacological and chemical chaperones could restore transport function to a certain degree. To investigate two potentially ER-bound, misfolded variants (D340G and R348W), we employed confocal and biochemical analyses. In addition, radiotracer uptake assays were conducted to assess whether pre-treatment with chaperones could restore transporter function. We show that pre-treatment of cells with the chemical chaperone 4-PBA (4-phenyl butyric acid) leads to increased membrane expression of misfolded variants and is associated with increased transport capacity of D340G (8-fold) and R348W (1.5 times) compared to untreated variants. We herein present proof of principle that folding-deficient SLC22 transporter variants, in particular those of OCT3, are amenable to rescue by chaperones. These findings need to be extended to other SLC22 members with corroborated disease associations.

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Sánchez-Fernández, Elena M., José M. García Fernández, and Carmen Ortiz Mellet. "Glycomimetic-based pharmacological chaperones for lysosomal storage disorders: lessons from Gaucher, GM1-gangliosidosis and Fabry diseases." Chemical Communications 52, no. 32 (2016): 5497–515. http://dx.doi.org/10.1039/c6cc01564f.

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Castellan, Tessa, Virginie Garcia, Frédéric Rodriguez, Isabelle Fabing, Yevhenii Shchukin, My Lan Tran, Stéphanie Ballereau, Thierry Levade, Yves Génisson, and Cécile Dehoux. "Concise asymmetric synthesis of new enantiomeric C-alkyl pyrrolidines acting as pharmacological chaperones against Gaucher disease." Organic & Biomolecular Chemistry 18, no. 39 (2020): 7852–61. http://dx.doi.org/10.1039/d0ob01522a.

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47

Norez, Caroline, Matteo Pasetto, Maria Cristina Dechecchi, Erika Barison, Cristina Anselmi, Anna Tamanini, Federica Quiri, et al. "Chemical conjugation of ΔF508-CFTR corrector deoxyspergualin to transporter human serum albumin enhances its ability to rescue Cl− channel functions." American Journal of Physiology-Lung Cellular and Molecular Physiology 295, no. 2 (August 2008): L336—L347. http://dx.doi.org/10.1152/ajplung.00059.2008.

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The most common mutation of the cystic fibrosis (CF) gene, the deletion of Phe508, encodes a protein (ΔF508-CFTR) that fails to fold properly, thus mutated ΔF508-cystic fibrosis transmembrane conductance regulator (CFTR) is recognized and degraded via the ubiquitin-proteasome endoplasmic reticulum-associated degradation pathway. Chemical and pharmacological chaperones and ligand-induced transport open options for designing specific drugs to control protein (mis)folding or transport. A class of compounds that has been proposed as having potential utility in ΔF508-CFTR is that which targets the molecular chaperone and proteasome systems. In this study, we have selected deoxyspergualin (DSG) as a reference molecule for this class of compounds and for ease of cross-linking to human serum albumin (HSA) as a protein transporter. Chemical cross-linking of DSG to HSA via a disulfide-based cross-linker and its administration to cells carrying ΔF508-CFTR resulted in a greater enhancement of ΔF508-CFTR function than when free DSG was used. Function of the selenium-dependent oxidoreductase system was required to allow intracellular activation of HSA-DSG conjugates. The principle that carrier proteins can deliver pharmacological chaperones to cells leading to correction of defective CFTR functions is therefore proven and warrants further investigations.

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Pereira, David M., Patrícia Valentão, and Paula B. Andrade. "Tuning protein folding in lysosomal storage diseases: the chemistry behind pharmacological chaperones." Chemical Science 9, no. 7 (2018): 1740–52. http://dx.doi.org/10.1039/c7sc04712f.

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Bernier, Virginie, Monique Lagacé, Michèle Lonergan, Marie-Françoise Arthus, Daniel G. Bichet, and Michel Bouvier. "Functional Rescue of the Constitutively Internalized V2 Vasopressin Receptor Mutant R137H by the Pharmacological Chaperone Action of SR49059." Molecular Endocrinology 18, no. 8 (August 1, 2004): 2074–84. http://dx.doi.org/10.1210/me.2004-0080.

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Abstract In most cases, nephrogenic diabetes insipidus results from mutations in the V2 vasopressin receptor (V2R) gene that cause intracellular retention of improperly folded receptors. We previously reported that cell permeable V2R antagonists act as pharmacological chaperones that rescue folding, trafficking, and function of several V2R mutants. More recently, the vasopressin antagonist, SR49059, was found to be therapeutically active in nephrogenic diabetes insipidus patients. Three of the patients with positive responses harbored the mutation R137H, previously reported to lead to constitutive endocytosis. This raises the possibility that, instead of acting as a pharmacological chaperone by favoring proper maturation of the receptors, SR49059 could mediate its action on R137H V2R by preventing its endocytosis. Here we report that the β-arrestin-mediated constitutive endocytosis of R137H V2R is not affected by SR49059, indicating that the functional rescue observed does not result from a stabilization of the receptor at the cell surface. Moreover, metabolic labeling revealed that R137H V2R is also poorly processed to the mature form. SR49059 treatment significantly improved its maturation and cell surface targeting, indicating that the functional rescue of R137H V2Rs results from the pharmacological chaperone action of the antagonist.

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Kato, Atsushi, Izumi Nakagome, Kasumi Sato, Arisa Yamamoto, Isao Adachi, Robert J. Nash, George W. J. Fleet, et al. "Docking study and biological evaluation of pyrrolidine-based iminosugars as pharmacological chaperones for Gaucher disease." Organic & Biomolecular Chemistry 14, no. 3 (2016): 1039–48. http://dx.doi.org/10.1039/c5ob02223a.

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